Materials and methods for the treatment of gastroesophageal reflux disease

ABSTRACT

The subject invention provides novel compounds and compositions for the safe and effective treatment of gastroesophageal reflux and related conditions. In a preferred embodiment, the compositions of the subject invention comprise esterified cisapride derivatives. These compositions possess potent activity in treating gastroesophageal reflux disease and substantially reduce adverse effects associated with the administration of cisapride. These adverse effects include, but are not limited to, diarrhea, abdominal cramping and elevations of blood pressure and heart rate.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application is a continuation of co-pending application Ser.No. 09/876,698, filed Jun. 7, 2001 (pending). The subject applicationalso claims priority to provisional application U.S. Serial No.60/209,926, filed Jun. 7, 2000.

BACKGROUND OF INVENTION

[0002] Cisapride is one of a class of compounds known as benzamidederivatives, the parent compound of which is metoclopramide. U.S. Pat.Nos. 4,962,115 and 5,057,525 (collectively “Van Daele” and incorporatedby reference in their entireties) disclose N-(3-hydroxy-4-piperidenyl)benzamides of cisapride. Van Daele discloses that these compounds, thepharmaceutically acceptable acid addition salts thereof and thestereochemically isomeric forms thereof, stimulate the motility of thegastrointestinal system.

[0003] As a class, these benzamide derivatives have several prominentpharmacological actions. The prominent pharmacological activities of thebenzamide derivatives are due to their effects on the neuronal systemswhich are modulated by the neurotransmitter serotonin. The role ofserotonin, and thus the pharmacology of the benzamide derivatives, hasbeen broadly implicated in a variety of conditions for many years. Thus,research has focused on locating the production and storage sites ofserotonin as well as the location of serotonin receptors in the humanbody in order to determine the connection between these sites andvarious disease states or conditions.

[0004] In this regard, it was discovered that a major site of productionand storage of serotonin is the enterochromaffin cell of thegastrointestinal mucosa. It was also discovered that serotonin has apowerful stimulating action on intestinal motility by stimulatingintestinal smooth muscle, speeding intestinal transit, and decreasingabsorption time, as in diarrhea. This stimulating action is alsoassociated with nausea and vomiting.

[0005] Because of their modulation of the serotonin neuronal system inthe gastrointestinal tract, many of the benzamide derivatives areeffective anti-emetic agents and are commonly used to control vomitingduring cancer chemotherapy or radiotherapy, especially when highlyemetogenic compounds such as cisplatin are used. This action is almostcertainly the result of the ability of the compounds to block theactions of serotonin (5HT) at specific sites of action, called the5HT3-receptor, which was classically designated in the scientificliterature as the serotonin M-receptor. Chemotherapy and radiationtherapy may induce nausea and vomiting by the release of serotonin fromdamaged enterochromaffin cells in the gastrointestinal tract. Release ofthe neurotransmitter serotonin stimulates both afferent vagal nervefibers (thus initiating the vomiting reflex) and serotonin receptors inthe chemoreceptor trigger zone of the area postrema region of the brain.The anatomical site for this action of the benzamide derivatives, andwhether such action is central (CNS), peripheral, or a combinationthereof, remains unresolved (Barnes et al., J. Pharm. Pharmacol. 40:586-588, 1988). Cisapride, like the other benzamide derivatives wouldappear to be an effective anti-emetic agent based on its ability tomodulate the activity of serotonin at the 5HT3 receptor.

[0006] A second prominent action of the benzamide derivatives is inaugmenting gastrointestinal smooth muscle activity from the esophagusthrough the proximal small bowel, thus accelerating esophageal and smallintestinal transit as well as facilitating gastric emptying andincreasing lower esophageal sphincter tone (Decktor et al., Eur. J.Pharmacol. 147: 313-316, 1988). Although the benzamide derivatives arenot cholinergic receptor agonists per se, the aforementioned smoothmuscle effects may be blocked by muscarinic receptor blocking agentssuch as atropine or neuronal transmission inhibitors of the tetrodotoxintype which affect sodium channels. Similar blocking activity has beenreported for the contractile effects of serotonin in the smallintestine. It is currently believed that the primary smooth muscleeffects of the benzamide derivatives are the result of an agonist actionupon a new class of serotonin receptors referred to as 5HT4 receptorswhich are located on interneurons in the myenteric plexus of the gutwall. Activation of these receptors subsequently enhances the release ofacetylcholine from parasympathetic nerve terminals located nearsurrounding smooth muscle fibers, and it is the combination ofacetylcholine with its receptors on smooth muscle membranes which is theactual trigger for muscle contraction.

[0007] Cisapride is presently used primarily to treat gastroesophagealreflux disease. This disease is characterized as the backward flow ofthe stomach contents into the esophagus. One of the most importantfactors in the pathogenesis of gastroesophageal reflux disease is areduction in the pressure barrier due to the failure of the loweresophageal sphincter. Failure of the lower esophageal sphincter canarise due to a low basal pressure, sphincter relaxation, or to anon-compensated increase in intragastric pressure. Other factors in thepathogenesis of the disease are delayed gastric emptying, insufficientesophageal clearing due to impaired peristalsis and the corrosive natureof the reflux material which can damage esophageal mucosa. Cisapride isthought to strengthen the anti-reflux barrier and improve esophagealclearance by increasing the lower esophageal sphincter pressure andenhancing peristaltic contractions.

[0008] Because of its activity as a prokinetic agent, cisapride wouldalso appear to be useful to treat dyspepsia, gastroparesis,constipation, post-operative ileus, and intestinal pseudo-obstruction.Dyspepsia is a condition characterized by an impairment of the power orfunction of digestion that can arise as a symptom of a primarygastrointestinal dysfunction or as a complication due to other disorderssuch as appendicitis, gallbladder disturbances, or malnutrition.Gastroparesis is a paralysis of the stomach brought about by a motorabnormality in the stomach or as a complication of diseases such asdiabetes, progressive systemic sclerosis, anorexia nervosa or myotonicdystrophy. Constipation is a condition characterized by infrequent ordifficult evacuation of feces resulting from conditions such as lack ofintestinal muscle tone or intestinal spasticity. Post-operative ileus isan obstruction in the intestine due to a disruption in muscle tonefollowing surgery. Intestinal pseudo-obstruction is a conditioncharacterized by constipation, colicky pain, and vomiting, but withoutevidence of physical obstruction.

[0009] Drug toxicity is an important consideration in the treatment ofhumans and animals. Toxic side effects (adverse effects) resulting fromthe administration of drugs include a variety of conditions which rangefrom low grade fever to death. Drug therapy is justified only when thebenefits of the treatment protocol outweigh the potential risksassociated with the treatment. The factors balanced by the practitionerinclude the qualitative and quantitative impact of the drug to be usedas well as the resulting outcome if the drug is not provided to theindividual. Other factors considered include the physical condition ofthe patient, the disease stage and its history of progression, and anyknown adverse effects associated with a drug.

[0010] Drug elimination is typically the result of metabolic activityupon the drug and the subsequent excretion of the drug from the body.Metabolic activity can take place within the vascular supply and/orwithin cellular compartments or organs. The liver is a principal site ofdrug metabolism. The metabolic process can be categorized into syntheticand nonsynthetic reactions. In nonsynthetic reactions, the drug ischemically altered by oxidation, reduction, hydrolysis, or anycombination of the aforementioned processes. These processes arecollectively referred to as Phase I reactions.

[0011] In Phase II reactions, also known as synthetic reactions orconjugations, the parent drug, or intermediate metabolites thereof, arecombined with endogenous substrates to yield an addition or conjugationproduct. Metabolites formed in synthetic reactions are, typically, morepolar and biologically inactive. As a result, these metabolites are moreeasily excreted via the kidneys (in urine) or the liver (in bile).Synthetic reactions include glucuronidation, amino acid conjugation,acetylation, sulfoconjugation, and methylation.

[0012] More than 90% of a dose of cisapride is metabolized by oxidativeN-dealkylation at the piperidine nitrogen or by aromatic hydroxylationoccurring on either the 4-fluorophenoxy or benzamide rings.

[0013] The administration of cisapride to a human has been found tocause adverse effects including, CNS disorders, increased systolicpressure, interactions with other drugs, diarrhea, and abdominalcramping. Further, it has been reported that intravenous administrationof cisapride demonstrates the occurrence of additional adverse (side)effects not experienced after oral administration of cisapride (Stacheret al. [1987] Digestive Diseases and Sciences 32(11):1223-1230). It isbelieved that these side effects are caused by the metabolites whichresult from the oxidative dealkylation or aromatic hydroxylation of thecompound which occurs in the cytochrome P-450 detoxification system.

[0014] Between July 1993 and December 1999, cisapride (PROPULSID,Janssen Pharmaceutica Products, L.P.) has been reportedly associatedwith at least 341 serious cardiac arrhythmias. These arrhythmias includeventricular tachycardia, ventricular fibrillation, torsades de pointes,and QT prolongation. Eighty (80) deaths have been reported. As a resultof these adverse effects, the product is being voluntarily withdrawnfrom the open market (in the United States) on Jul. 14, 2000; however,the drug will be available through an investigational limited accessprogram.

[0015] Thus, it would be particularly desirable to provide compoundswith the therapeutic advantages of cisapride which would not have theaforementioned disadvantages.

BRIEF SUMMARY

[0016] The subject invention provides novel compounds and compositionsfor the safe and effective treatment of gastroesophageal reflux andrelated conditions. In a preferred embodiment, the compositions of thesubject invention comprise esterified cisapride derivatives. Thesecompositions possess potent activity in treating gastroesophageal refluxdisease and substantially reduce adverse effects associated with theadministration of cisapride. These adverse effects include, but are notlimited to, diarrhea, abdominal cramping and elevations of bloodpressure and heart rate.

[0017] Additionally, the novel compositions of the subject invention areuseful in treating emesis and other conditions, including but notlimited to dyspepsia, gastroparesis, constipation, and intestinalpseudo-obstruction. As an added benefit, adverse effects associated withthe administration of cisapride are also reduced in these methods oftreatment.

[0018] Advantageously, the subject invention provides compounds whichare readily metabolized by the physiological metabolic drugdetoxification systems. Specifically, in a preferred embodiment, thetherapeutic compounds of the subject invention contain a moiety, whichdoes not detract from the ability of these compounds to provide atherapeutic benefit, but which makes these compounds more susceptible todegradation by hydrolases. Specifically exemplified are compounds whichcontain an ester group making them susceptible to degradation by serumand/or cytosolic esterases, thereby avoiding the cytochrome P-450 drugdetoxification system associated with adverse effects caused bycisapride and reducing the incidence of adverse events.

[0019] The subject invention further provides methods of treatmentcomprising the administration of these compounds to individuals in needof treatment for gastroesophageal reflux disease and related conditions.

[0020] Advantageously, the therapeutic compounds of the subjectinvention are stable in storage and provide for safer metabolism of thedrugs as compared to other drugs which are available for treatment ofgastroesophageal reflux, dyspepsia, gastroparesis, constipation,post-operative ileus, and intestinal pseudo-obstruction; therefore, thecompounds of the subject invention can be used with a lower incidence ofside effects and toxicity.

[0021] In a further embodiment, the subject invention pertains to thebreakdown products which are formed when the therapeutic compounds ofthe subject invention are acted upon by hydrolases. These breakdownproducts can be used as described herein to monitor the clearance of thetherapeutic compounds from a patient.

[0022] In yet a further embodiment, the subject invention providesmethods for synthesizing the therapeutic compounds of the subjectinvention.

DETAILED DISCLOSURE

[0023] The subject invention provides novel compounds which are moreeasily metabolized by the metabolic drug detoxification systems. Thisinvention is also drawn to methods of treating disorders, such asgastroesophageal reflux disease, and related conditions. Specifically,the subject invention provides analogs of cisapride which have beendesigned to be more susceptible to degradation by hydrolases,particularly serum and/or cytosolic esterases and methods of treatmentcomprising the administration of these analogs to individuals.

[0024] Advantageously, the therapeutic compounds of the subjectinvention are stable in storage but have a relatively short half-life inthe physiological environment; therefore, the compounds of the subjectinvention can be used with a lower incidence of side effects andtoxicity.

[0025] In a preferred embodiment of the subject invention, therapeuticcompounds are provided which are useful in the treatment ofgastroesophageal reflux disease and which contain a moiety, such as anester group, which is susceptible to degradation by hydrolases, therebybreaking down the compound and facilitating its efficient removal fromthe treated individual. In a preferred embodiment, the therapeuticcompounds are metabolized by the Phase I drug detoxification system.

[0026] A further aspect of the subject invention pertains to thebreakdown products which are produced when the therapeutic compounds ofthe subject invention are acted upon by a hydrolase. The presence ofthese breakdown products in the urine or serum can be used to monitorthe rate of clearance of the therapeutic compound from a patient.

[0027] Degradation of the compounds of the subject invention by enzymessuch as hydrolases (esterases, peptidases, lipases, glycosidases,phosphateases, etc.) is particularly advantageous for drug metabolismbecause these enzymes are ubiquitously distributed and their activity isnot dependent on age, gender, or disease state to the same extent asoxidative hepatic drug metabolism.

[0028] The subject invention further provides methods of treatingdisorders, such as gastroesophageal reflux disease comprising theadministration of a therapeutically effective amount of cisaprideanalogs to an individual in need of treatment. In a specific embodiment,the subject invention provides esterified cisapride analogs andpharmaceutical compositions of these esterified compounds.

[0029] The subject invention further provides materials and methods forthe treatment of emesis and such other conditions, including but notlimited to dyspepsia, gastroparesis, constipation, and intestinalpseudo-obstruction, while substantially reducing adverse effectsassociated with the administration of cisapride.

[0030] In a preferred embodiment of the subject invention, therapeuticcompounds are provided which are useful in the treatment ofgastroesophageal reflux, dyspepsia, gastroparesis, constipation,post-operative ileus, and intestinal pseudo-obstruction and whichcontain an ester group which is acted upon by esterases thereby breakingdown the compound and facilitating its efficient removal from thetreated individual.

[0031] The subject invention further provides methods of synthesizingthe unique and advantageous therapeutic compounds of the subjectinvention. Particularly, methods of producing less toxic therapeuticagents comprising introducing ester groups into therapeutic agents(target drugs) are taught. The ester linkage may be introduced into thecompound at a site which is convenient in the manufacturing process forthe target drug. Additionally, the sensitivity of the ester linkage maybe manipulated by the addition of side groups which hinder or promotethe hydrolytic activity of the hydrolases or esterases responsible forcleaving the drug at the ester locus. Methods of adding such sidegroups, as well as the side groups themselves, are well known to theskilled artisan and can be readily carried out utilizing the guidanceprovided herein.

[0032] The chemical synthesis of the disclosed analogs of cisapride canbe performed by the method described in European Patent Application No.0,076,530 A2 published Apr. 13, 1983, U.S. Pat. Nos. 4,962,115 and5,057,525 and in Van Daele et al., Drug Development Res. 8: 225-232(1986), the disclosures of which are incorporated herein by reference intheir entireties, and modified by the incorporation of an ester group ata point convenient in the synthesis of the disclosed compounds.Exemplary, non-limiting synthesis schemes for certain esterifiedcisapride analogs of the subject invention are provided below.

[0033] The present invention is concerned with novelN-(4-piperidinyl)benzamides having the general Formula (I) and theirpharmaceutically acceptable salts.

[0034] Wherein:

[0035] R₁ is H, Cl ₄ alkyl, OH, OC₁₋₄alkyl, —COOH, —COOC₁₋₄alkyl,—O(C═O)OC₁₋₄alkyl, —O(C═O)C₁₋₄alkyl, or —C₁₄alkylNR₇R₈ where R₇ and R₈are, independently, H or C₁₋₄ alkyl;

[0036] R₂ is H, C₁₋₄ alkyl, —OC₁₋₄alkyl, —COOH, or —(C═O)OC₁₋₄alkyl;

[0037] X is O or N;

[0038] R₁ and X are in the cis- or trans-configuration;

[0039] R₃ is H or C₁₋₃ alkyl (if X is an oxygen atom, then R₃ does notexist);

[0040] R₄, R₅, and R₆ are each, independently, selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, OC₁₋₄alkyl, halogen atom, hydroxy,cyano, nitro, amino, mono- and di(lower alkyl)amino, aminocarbonyl,arylcarbonylamino, alkylcarbonylamino, lower-alkyl carbonyl, lower-alkylcarbonyloxy, aminosulfonyl, lower-alkylsulfinyl, lower-alkylsulfonyl,lower-alkylthio and mercapto; and

[0041] wherein L has the formula—C_(n)H_(2n)—X—CmH_(2m)—(CR₉R₁₀)_(p)—(C═O)O—Y, wherein

[0042] n is an integer from 1 to 4 inclusive;

[0043] X is —CH(OH)—, —NH—, —S—, —O—, or a direct bond;

[0044] m is an integer from 0 to 4 inclusive;

[0045] p is 0 or 1;

[0046] R₉ and R₁₀ are, independently, H, C₁₋₄ alkyl, or R₉R₁₀ are linkedand together form a 5- or a 6-membered cycloalkyl ring; and

[0047] Y is H, C₁₋₄ alkyl or cycloalkyl optionally substituted by 1 ormore (2 to 8) heteroatoms selected from the group consisting of O; N; S;or aryl or heteroaryl optionally substituted by 1 or more (2 to 8)halogen atoms, C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxy, cyano, amino,alkylamino, dialkylamino, trifluoromethyl, —COOH, or —COOC₁₋₄alkyl (whenY is hydrogen, the compounds can also be quaternary ammonium complexessuch as tetrabutyl or tetraethylammonium and trigonellinium).

[0048] Those skilled in the art will recognize that the structure ofFormula I has at least 2 asymmetric centers at the 3- and 4-positions ofthe piperidine ring (carbon atoms bearing the R₁ and R₂ groups).Substituents on the piperidinyl ring can have the cis- or thetrans-configuration. Accordingly, the subject invention includes the 4individual enantiomers associated with these 2 carbon centers, namelythe 3R,4R; 3S,4S; 3R,4S; and 3S,4R conformations.

[0049] Preferred compounds are those wherein R₄, R₅, and R₆ are,independently, selected from the group consisting of halo, amino, mono-and dialkylamino, and lower alkyloxy.

[0050] Particularly preferred compounds are those wherein R₄ is methoxy,R₅ is amino or methylamino, and R₅ is chloro, in the 2-, 4-, and5-position of the phenyl ring, respectively.

[0051] Particularly, preferred compounds of the subject inventioninclude those where: R₁═OCH₃; R₂═H; X═O or N (if X═N, then R₃=H); R₄,R₅, and R₆ are methoxy, amino, and chlorine at the 2, 4, and 5-positionof the phenyl ring, respectively. RI and X are in the cis-configuration.

[0052] Preferred compounds within the scope of this invention have thecis-configuration.

[0053] Particularly preferred compounds of this invention have thefollowing formulae:

[0054] where IIIa and IIIb are mirror images of each other(enantiomers), and where L is defined as shown in Formula (II):

[0055] where n=1 to 4, m=0 to 4, X is a direct bond and Y is hydrogen,lower alkyl, or substituted aryl.

[0056] In the most preferred compounds, n—2, m=0, X is a direct bond,and Y is hydrogen, methyl, ethyl, isopropyl, sec-butyl, or4-fluorophenyl.

[0057] The compounds of Formula I can generally be prepared by thereaction of an amine of Formula (IV) with a carboxylic acid of Formula(V).

[0058] Functional derivatives of the carboxylic acids shown as Formula(V) can also be used, as would be known to persons skilled in the art ofsynthetic chemistry. Suitable functional derivatives include acylhalides, anhydrides, and esters. The reaction conditions for mixing (IV)and (V) to produce (I) are well known conditions to the ordinary skilledsynthetic chemist.

[0059] The compounds of Formula I wherein R₁ is hydrogen and thesubstituents in the 3- and 4-positions of the piperidine ring have thetrans configuration, said compounds being represented by the Formula(Ia), can be prepared by reacting a 7-oxo-3-azabicyclo[4,1,0]heptane ofFormula (VI) with a benzamide of Formula (VII). These compounds can befurther alkylated in order to obtain a product wherein R₁ is other thanhydrogen.

[0060] The compounds of Formula (I) wherein the substituents in the 3-and 4-positions of the piperidine ring have the cis configuration, saidcompounds being represented by the Formula (Ib), can be prepared by thereductive alkylation of a piperidone of Formula (VIII) with a benzamideof Formula (VII). This approach is applicable only when R₂ is hydrogen.Another approach, which is applicable whether R₂ is hydrogen or loweralkyl, is to react an amine of Formula (IX), having the 3- and4-substituents of the piperidine ring in the cis configuration, with acarboxylic acid of Formula (V) or a suitable functional derivativethereof (an ester, an anhydride, or an acyl chloride for example).

[0061] The compounds of this invention have therapeutic propertiessimilar to those of the unmodified parent compounds. Accordingly, dosagerates and routes of administration of the disclosed compounds aresimilar to those already used in the art and known to the skilledartisan (see, for example, Physicians' Desk Reference, 54th Ed., MedicalEconomics Company, Montvale, N.J., 2000).

[0062] The magnitude of a prophylactic or therapeutic dose of esterifiedcisapride in the acute or chronic management of diseases and/ordisorders described herein will vary with the severity of the conditionto be treated, and the route of administration. The dose, and perhapsthe dose frequency, will also vary according to the age, body weight,and response of the individual patient. In general, the total daily doserange for esterified cisapride, for the conditions described herein, isfrom about 1 mg to about 200 mg, in single or divided doses. Preferably,a daily dose range should be between about 5 mg to about 100 mg, insingle or divided doses, while most preferably, a daily dose rangeshould be between about 5 mg to about 75 mg, in single or divided doses.It is preferred that the doses are administered from 1 to 4 times a day.In managing the patient, the therapy should be initiated at a lowerdose, perhaps about 5 mg to about 10 mg, and increased up to about 50 mgor higher depending on the patient's global response. It is furtherrecommended that children, and patients over 65 years, and those withimpaired renal or hepatic function, initially receive low doses, andthat they be titrated based on individual response(s) and bloodlevel(s). It may be necessary to use dosages outside these ranges insome cases as will be apparent to those skilled in the art. Further, itis noted that the clinician or treating physician will know how and whento interrupt, adjust, or terminate therapy in conjunction withindividual patient response.

[0063] The compounds of the subject invention can be formulatedaccording to known methods for preparing pharmaceutically usefulcompositions. Formulations are described in detail in a number ofsources which are well known and readily available to those skilled inthe art. For example, Remington's Pharmaceutical Science by E. W. Martindescribes formulations which can be used in connection with the subjectinvention. In general, the compositions of the subject invention areformulated such that an effective amount of the bioactive compound(s) iscombined with a suitable carrier in order to facilitate effectiveadministration of the composition.

[0064] The compositions of the subject invention include compositionssuch as suspensions, solutions and elixirs; aerosols; or carriers suchas starches, sugars, microcrystalline cellulose, diluents, granulatingagents, lubricants, binders, disintegrating agents, and the like, in thecase of oral solid preparations (such as powders, capsules, and tablets)with the oral solid preparations being preferred over the oral liquidpreparations. A preferred oral solid preparation is capsules. The mostpreferred oral solid preparation is tablets. Preferred amounts of activeingredient (i.e., an esterified cisapride analog) in a solid dosage formare about 5 mg, 10 mg, and 25 mg.

[0065] Further, acceptable carriers can be either solid or liquid. Solidform preparations include powders, tablets, pills, capsules, cachets,suppositories and dispersible granules. A solid carrier can be one ormore substances which may act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents or encapsulating materials.

[0066] The disclosed pharmaceutical compositions may be subdivided intounit doses containing appropriate quantities of the active component.The unit dosage form can be a packaged preparation, such as packetedtablets, capsules, and powders in paper or plastic containers or invials or ampules. Also, the unit dosage can be a liquid basedpreparation or formulated to be incorporated into solid food products,chewing gum, or lozenge.

[0067] In addition to the common dosage forms set out above, thecompounds of the present invention may also be administered bycontrolled release means and/or delivery devices such as those describedin U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and4,008,719, the disclosures of which are hereby incorporated by referencein their entirety.

[0068] Any suitable route of administration may be employed forproviding the patient with an effective dosage of esterified cisapride.For example, oral, rectal, parenteral (subcutaneous, intramuscular,intravenous), transdermal, and like forms of administration may beemployed. Dosage forms include tablets, troches, dispersions,suspensions, solutions, capsules, patches, and the like.

[0069] One embodiment of the invention provides a method of treatinggastroesophageal reflux disease in a mammal, while substantiallyreducing the concomitant adverse effects associated with theadministration of cisapride, which comprises administering to a human inneed of such treatment, a therapeutically effective amount of esterifiedcisapride, or a pharmaceutically acceptable salt thereof. A preferredembodiment is the treatment of gastroesophageal reflux disease inhumans.

[0070] Another embodiment of the invention provides a composition forthe treatment of a human suffering from gastroesophageal reflux disease,which comprises a therapeutically effective amount of esterifiedcisapride, or a pharmaceutically acceptable salt thereof.

[0071] Yet another embodiment of the present invention provides a methodof eliciting an anti-emetic effect in a mammal, while substantiallyreducing the adverse effects associated with the administration ofcisapride, which comprises administering to a mammal in need of suchanti-emetic therapy, a therapeutically effective amount of esterifiedcisapride, or a pharmaceutically acceptable salt thereof. Preferably,the mammal is a human.

[0072] In an additional embodiment, the present invention encompasses ananti-emetic composition for the treatment of a mammal in need ofanti-emetic therapy, which comprises a therapeutically effective amountof esterified cisapride, or a pharmaceutically acceptable salt thereof.

[0073] A further aspect of the present invention includes a method oftreating a condition caused by gastrointestinal motility dysfunction ina mammal which comprises administering to a mammal in need of treatmentfor gastrointestinal motility dysfunction, a therapeutically effectiveamount of esterified cisapride, or a pharmaceutically acceptable saltthereof. Conditions caused by gastrointestinal motility dysfunctioninclude, but are not limited to, dyspepsia, gastroparesis, constipation,post-operative ileus, and intestinal pseudo-obstruction. Preferably, themammal is a human.

[0074] The observation that cisapride enters the central nervous systemand binds to 5HT4 receptors indicates that cisapride may havecentrally-mediated effects. Cisapride is a potent ligand at 5HT4receptors, and these receptors are located in several areas of thecentral nervous system. Modulation of serotonergic systems has a varietyof behavioral effects. According, the compounds of the subject inventioncan be used in the treatment of: 1) cognitive disorders, including butnot limited to Alzheimer's disease; 2) behavioral disorders, includingbut not limited to schizophrenia, mania, obsessive-compulsive disorder,and psychoactive substance use disorders; 3) mood disorders, includingbut not limited to depression and anxiety; and 4) disorders of controlof autonomic function, including but not limited to essentialhypertension and sleep disorders.

[0075] Accordingly, the present invention also provides methods oftreating cognitive, behavioral, mood, or autonomic function controldisorders in a mammal comprising the administration of a therapeuticallyeffective amount of esterified cisapride, or a pharmaceuticallyacceptable salt thereof. Preferably, the mammal is a human.

[0076] The term “pharmaceutically acceptable salts” or “apharmaceutically acceptable salt thereof” refer to salts prepared frompharmaceutically acceptable non-toxic acids or bases including inorganicacids and bases and organic acids and bases. Since the compound of thepresent invention is basic, salts may be prepared from pharmaceuticallyacceptable non-toxic acids. Suitable pharmaceutically acceptable acidaddition salts for the compound of the present invention include acetic,benzenesulfonic (besylate), benzoic, camphorsulfonic, citric,ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaricacid, p-toluenesulfonic, and the like. Preferred acid addition salts arethe chloride and sulfate salts. In the most preferred embodiment,esterified cisapride analogs are administered as the free base.

[0077] The term “therapeutically effective amount” means: 1) an amountsufficient to alleviate reflux disease, 2) an amount sufficient toalleviate nausea and vomiting, or 3) an amount sufficient to alleviate acondition caused by gastrointestinal motility dysfunction.Therapeutically effective amounts of esterified cisapride areencompassed by the above-described dosage amounts and dose frequencyschedule.

[0078] A “mammal” may be, for example, a mouse, rat, pig, horse, rabbit,goat, pig, cow, cat, dog, or human. In a preferred embodiment, themammal is a human.

[0079] The term “individual(s)” is defined as a single mammal to whichis administered a compound of the present invention. The mammal may be arodent, for example a mouse or rat, pig, horse, rabbit, goat, pig, cow,cat, dog, or human. In a preferred embodiment, the individual is ahuman.

[0080] The term “esterified cisapride” means therapeutic compounds ofthe subject invention which contain an ester group which does notdetract from the ability of these compounds to provide a therapeuticbenefit, but which makes these compounds more susceptible to degradationby hydrolases, particularly serum and/or cytosolic esterases, and whichreduces the interaction of the cytochrome P-450 drug detoxificationsystem with the cisapride compounds. Esterase mediated metabolism of theesterified cisapride compounds reduces the role of the cytochrome P-450drug detoxification system in cisapride metabolism and reduces oreliminates adverse effects caused by cisapride.

[0081] The term “adverse effects” includes, but is not limited to,gastrointestinal disorders such as diarrhea, abdominal cramping, andabdominal grumbling; tiredness; headache; increased systolic pressure;death; ventricular tachycardia; ventricular fibrillation; torsades depointes; QT prolongation; increased heart rate; neurological and CNSdisorders; and interaction of cisapride with other drugs givenconcurrently such as digoxin, diazepam, ethanol, acenocoumarol,cimetidine, ranitidine, paracetamol, and propranolol.

[0082] The term “gastroesophageal reflux disease” as used herein meansthe incidence of, and the symptoms of, those conditions causing thebackward flow of the stomach contents into the esophagus.

[0083] The terms “eliciting an anti-emetic effect” and “anti-emetictherapy” as used herein mean providing relief from or preventing thesymptoms of nausea and vomiting induced spontaneously or associated withemetogenic cancer chemotherapy or irradiation therapy.

[0084] The term “treating a condition caused by gastrointestinalmotility dysfunction” as used herein means treating the symptoms andconditions associated with this disorder which include, but are notlimited to, dyspepsia, gastroparesis, constipation, post-operativeileus, and intestinal pseudo-obstruction.

[0085] The term “prokinetic” as used herein means the enhancement ofperistalsis in, and thus the movement through the gastrointestinaltract.

[0086] The term “dyspepsia” as used herein means a conditioncharacterized by an impairment of the power or function of digestionthat can arise as a symptom of a primary gastrointestinal dysfunction oras a complication due to other disorders such as appendicitis,gallbladder disturbances, or malnutrition.

[0087] The term “gastroparesis” as used herein means a paralysis of thestomach brought about by a motor abnormality in the stomach or as acomplication of diseases such as diabetes, progressive systemicsclerosis, anorexia nervosa, or myotonic dystrophy.

[0088] The term “constipation” as used herein means a conditioncharacterized by infrequent or difficult evacuation of feces resultingfrom conditions such as lack of intestinal muscle tone or intestinalspasticity.

[0089] The term “post-operative ileus” as used herein means anobstruction in the intestine due to a disruption in muscle tonefollowing surgery.

[0090] The term “intestinal pseudo-obstruction” as used herein means acondition characterized by constipation, colicky pain, and vomiting, butwithout evidence of physical obstruction.

[0091] All patents, patent applications, provisional applications, andpublications referred to or cited herein are incorporated by referencein their entirety to the extent they are not inconsistent with theexplicit teachings of this specification.

[0092] Following is an example which illustrates procedures forpracticing the invention. This example should not be construed aslimiting. All percentages are by weight and all solvent mixtureproportions are by volume unless otherwise noted.

EXAMPLE 1 Synthesis of Specific Compounds of the Subject Invention

[0093] Preferred compounds of the subject invention have the Formula(lb) where the substituents at the 3- and 4-positions of the piperidinering have the cis-configuration, R₁ is methoxy, R₂ is hydrogen, R₄ ismethoxy, R₅ is amino, R₆ is chloro in the 2-, 4-, and 5-positions of thebenzamide ring, respectively. In particularly preferred compounds, L hasthe Formula (II) wherein n=2, m=O, X is a direct bond, and Y ishydrogen, methyl, ethyl, isopropyl, sec-butyl, or 4-fluorophenyl. Thecommon intermediate to these preferred compounds is compound 9 asdescribed below.

[0094] The synthesis can be described in more details as follows:

[0095] 1-carbethoxy-4-piperidone 1 reacts with bromine in an inertsolvent such as dichloromethane to give high yields of1-carbethoxy-3-bromo-4-piperidone 2. The bromo compound 2 reacts withsodium methoxide in methanol to give1-carbethoxy-3-hydroxy-4,4-dimethoxypiperidine 3, which in turn isalkylated to the corresponding 3-methoxy analog 4 with iodomethane indimethylformamide in the presence of sodium hydride. The ketal 4 ishydrolyzed to 1-carbethoxy-3-methoxy-4-piperidone 5 by stirring in 1%sulfuric acid at room temperature. The amine 6 of cis-configuration isthen readily obtained by reductive alkylation of 5 with benzylamine inthe presence of hydrogen gas and 10% Pd/C with a small amount ofthiophene. Further hydrogenolysis of the benzyl moiety with Pd/C and nothiophene gives the primary amine 7. Compound 7 in turn reacts with thecommercially available 4-amino-5-chloro-2-methoxybenzoic acid in thepresence of DCC and dimethyaminopyridine in dichloromethane to give thebenzamide 8. Compound 8 is then hydrolyzed to the intermediate 2 withpotassium hydroxide in ethanol/water.

[0096] The intermediate 9 reacts with acrylic acid or an ester thereofin the presence of a base such as diethylamine to give the finalcompounds 11 (see diagram below).

[0097] For example: Acryloyl chloride and 4-fluorophenol react indichloromethane in the presence of triethylamine to give 4-fluorophenylacrylate 10 (R=4-fluorophenyl). Compound 10 is then added to a solutionof 2 in ethanol and diethylamine to give 11 (R=4-fluorophenyl) afterusual workup.

EXAMPLE 2 Additional Synthesis Protocols

[0098] In addition to the general synthetic methods described above, thefollowing procedures can also be utilized:

[0099] The compounds of Formula (I) wherein X is oxygen and RI ismethoxy can be prepared by reduction of a compound of Formula (VIII)with sodium borohydride in lower alkanol solvent, followed by couplingof the resulting alcohol (X) with a substituted benzoic acid of Formula(V) in the presence of a coupling reagent such as a dialkylcarbodiimide.

[0100] Compounds of Formula I where L is CH₂CHMeCOOR can be prepared byreacting the amine intermediate IX with methacrylic acid or an esterthereof, optionally in the presence of a base such as Triton B ortriethylaamine.

[0101] Compounds of Formula I where L is CH₂CMe₂COOR can be preparedaccording to Katritzky et al., Synthesis (1989), 747 by reacting thebenzotriazolylmethyl derivative of the amine intermediate IX with a2-bromoisobutyric acid ester in the presence of zinc and trimethylsilylchloride.

[0102] Compounds of Formula I where L is CH₂COOR are prepared byalkylating intermediate IX with bromoacetic acid or an ester thereof inthe presence of a base such as potassium carbonate or triethylamine inan inert solvent such as tetrahydrofuran or dimethylformamide.

[0103] Compounds of Formula I where L is (CH₂)₃COOR can be made byalkylating intermediate IX with 4-bromobutyric acid or an ester thereofin the presence of a base such as potassium carbonate or triethylaminein an inert solvent such as tetrahydrofuran or dimethylformamide.

EXAMPLE 3 Additional Synthesis Procedures

[0104]3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-propionicAcid

[0105] A solution of4-amino-5-chloro-2-methoxy-N-(3-methoxy-piperidin-4-yl)-benzamide (1 g,3.2 mmol), and 241 uL of acrylic acid in 50 ml dichloromethane wasstirred under nitrogen for 6 hr then concentrated in vacuo. The residuewas slurried with hot ethyl acetate and filtered at room temperature toyield 1.15 g of product as a white solid.

[0106] Substituting Methacrylic Acid for Acrylic Acid Provided:

[0107]3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-2-methyl-propionicAcid

EXAMPLE 4 Additional Synthesis Procedures

[0108]3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-propionicAcid Methyl Ester

[0109] A solution of 640 mg of3-[4-(4-Amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-propionicacid in 20 ml methanol was treated with 1 ml sulfuric acid and heated atreflux under argon for 3 hr. The mixture was diluted with sodiumcarbonate solution, extracted into dichloromethane dried over sodiumsulfate, and concentrated in vacuo to provide 600 mg of crude ester asan oil. Trituration with methanol/ethyl acetate afforded a crystallinesolid.

[0110] The following compounds can be similarly prepared:

[0111]3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-propionicacid ethyl ester

[0112]3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-propionicacid isopropyl ester

[0113]3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-propionicacid 2-methoxy-ethyl ester

[0114]3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-propionicacid cyclohexyl ester

[0115]3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-2-methyl-propionicacid ethyl ester

[0116]3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-2-methyl-propionicacid isopropyl ester

[0117]3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-2-methoxy-propionicacid 2-methoxy-ethyl ester

[0118]3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-pieridin-1-yl]-2-methyl-propionicacid cyclohexyl ester

EXAMPLE 5 Additional Synthesis Procedure

[0119][4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-aceticacid methyl ester

[0120] A mixture containing 313 mg norcisapride and 276 mg potassiumcarbonate in 10 ml DMF was treated with 153 mg of bromo-acetic acidmethyl ester. The reaction was stirred at ambient temperature for 8 hr.Extractive workup with waterdichloromethane followed by flashchromatography afforded 455 mg of product.

[0121] The following compounds can be similarly prepared:

[0122][4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-aceticacid phenyl ester

[0123][4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-aceticacid 4-fluoro-benzyl ester

EXAMPLE 60 Additional Synthesis Procedures

[0124]4-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-butyricacid ethyl ester

[0125] A mixture containing 313 mg norcisapride, 276 mg potassiumcarbonate, and a pinch of sodium iodide in 10 ml DMF was treated with195 mg 4-bromo-butyric acid ethyl ester. The reaction was stirred atambient temperature for 14 hr. Extractive workup withwater/dichloromethane followed by flash chromatography afforded 230 mgof product.

[0126] The following compounds can be similarly prepared:

[0127][4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-butyricacid phenyl ester

[0128][4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-butyricacid 4-fluoro-benzyl ester

EXAMPLE 7 Activity Assay

[0129] A segment of oesophagus obtained from Wistar derived male orfemale rats weighing 270±25 g and sacrificed by CO₂ overexposure isused. The tissue is placed under 1 g tension in a 10 mL bath containing3 IM indomethacin and 1 μM ketanserin in Krebs solution pH 7.4 and at32° C. and submaximal tonic isometrically recorded contraction isinduced by carbachol (1 μM). Test substance (30 μM)-induced relaxationby 50 percent or more (≧50%) within 5 min, relative to control 0.3 μMserotonin (5-HT) response, indicates possible receptor agonist activity.

[0130] At a test substance concentration where no significant agonistactivity is seen, ability to reduce the serotonin-induced relaxatantresponse by 50 percent or more (≧50%) indicates receptor antagonistactivity.

[0131] It should be understood that the examples and embodimentsdescribed herein are for illustrative purposes only and that variousmodifications or changes in light thereof will be suggested to personsskilled in the art and are to be included within the spirit and purviewof this application and the scope of the appended claims. Further, allpatents, patent applications, provisional applications, and publicationsreferred to or cited herein are incorporated by reference in theirentirety to the extent they are not inconsistent with the explicitteachings of this specification.

1. A method for treating a disease state which can be improved bystimulating the motility of the gastrointestinal system wherein saidmethod comprises administering, to an individual in need of such atreatment, a compound, or an analog or salt thereof, wherein saidcompound has the following structure:

wherein: R₁ is H, C₁₋₄ alkyl, OH, OC₁₋₄alkyl, —COOH, —COOC₁₋₄alkyl,—O(C═O)OC₁₋₄alkyl, —O(C═O)C₁₋₄alkyl, or —C₁₋₄alkylNR₇R₈ where R₇ and R₉are, independently, H or C₁₋₄ alkyl; R₂ is H, C₁₋₄ alkyl, —OC₁₋₄alkyl,—COOH, or —(C═O)OC₁₋₄alkyl; X is O or N; R₃ is H or C₁₋₃ alkyl (if X isan oxygen atom, then R₃ does not exist); R₄, R₅, and R₆ are each,independently, selected from the group consisting of hydrogen, C₁₋₄alkyl, —OC₁₋₄alkyl, halogen atom, hydroxy, cyano, nitro, amino, mono-and di(lower alkyl)amino, aminocarbonyl, arylcarbonylamino,alkylcarbonylamino, lower-alkyl carbonyl, lower-alkyl carbonyloxy,aminosulfonyl, lower-alkylsulfinyl, lower-alkylsulfonyl, lower-alkylthioand mercapto; and wherein L has the formula—C_(n)H_(2n)—X—C_(m)H_(2m)—(CR₉R₁₀)_(p)—(C═O)O—Y, wherein n is aninteger from 1 to 4 inclusive; X is —CH(OH)—, —NH—, —S—, —O—, or adirect bond; m is an integer from 0 to 4 inclusive; p is 0 or 1; R₉ andR₁₀ are, independently, H, C₁₋₄ alkyl, or R₉R₁₀ are linked and togetherform a 5- or a 6-membered cycloalkyl ring; and Y is H, C₁₋₄ alkyl orcycloalkyl optionally substituted by 1 or more heteroatoms selected fromthe group consisting of O; N; S; or aryl or heteroaryl optionallysubstituted by 1 or more halogen atoms, C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxy,cyano, amino, alkylamino, dialkylamino, trifluoromethyl, —COOH, or—COOC₁₋₄alkyl.
 2. The method, according to claim 1, wherein said diseasestate is selected from the group consisting of gastroesophageal refluxdisease, dyspepsia, gastroparesis, constipation, post-operative ileus,and intestinal pseudo-obstruction.
 3. The method, according to claim 2,wherein said disease state is gastroesophageal reflux disease.
 4. Themethod, according to claim 1, wherein said individual is a human.
 5. Themethod, according to claim 1, wherein R₄, R₅, and R₆ are, independently,selected from the group consisting of halo, amino, mono- anddialkylamino, and lower alkyloxy.
 6. The method, according to claim 1,wherein R₄ is methoxy, R₅ is amino or methylamino, and R₆ is chloro, inthe 2-, 4-, and 5-position of the phenyl ring, respectively.
 7. Themethod, according to claim 1, wherein said compound is selected from thegroup consisting of:

where IIIa and IIIb are mirror images of each other (enantiomers), andwhere L is defined as shown in Formula (II):

where n—1 to 4, m—O to 4, X is a direct bond and Y is hydrogen, loweralkyl, or substituted aryl.
 8. The method, according to claim 1, whereinR₁═OCH₃; R₂—H; X═O or N (if X═N, then R₃═H); R₄, R₅, and R₆ are methoxy,amino, and chlorine at the 2, 4, and 5-position of the phenyl ring,respectively.
 9. The method, according to claim 1, wherein bothasymmetric centers are in the cis-configuration.
 10. A compound, or ananalog or salt thereof, wherein said compound has the followingstructure:

wherein: R₁ is H, C₁₋₄ alkyl, OH, OC₁₋₄alkyl, —COOH, —COOC₁₋₄alkyl,—O(C═O)OC₁₋₄alkyl, —O(C═O)C₁₋₄alkyl, or —C₁₋₄alkylNR₇R₈ where R₇ and R₈are, independently, H or C₁₋₄ alkyl; R₂ is H, C₁₋₄ alkyl, —OC₁₋₄alkyl,—COOH, or —(C═O)OC₁₋₄alkyl; X is O or N; R₃ is H or C₁₋₃ alkyl (if X isan oxygen atom, then R₃ does not exist); R₄, R₅, and R₆ are each,independently, selected from the group consisting of hydrogen, C₁₋₄alkyl, —OC₁₋₄alkyl, halogen atom, hydroxy, cyano, nitro, amino, mono-and di(lower alkyl)amino, aminocarbonyl, arylcarbonylamino,alkylcarbonylamino, lower-alkyl carbonyl, lower-alkyl carbonyloxy,aminosulfonyl, lower-alkylsulfinyl, lower-alkylsulfonyl, lower-alkylthioand mercapto; and wherein L has the formula—C_(n)H_(2n)—X—C_(m)H_(2m)—(CR₉R₁₀)_(p)—(C═O)O—Y, wherein n is aninteger from 1 to 4 inclusive; X is —CH(OH)—, —NH—, —S—, —O—, or adirect bond; m is an integer from 0 to 4 inclusive; p is 0 or 1; R₉ andR₁₀ are, independently, H, C₁₋₄ alkyl, or R₉R₁₀ are linked and togetherform a 5- or a 6-membered cycloalkyl ring; and Y is H, C₁₋₄ alkyl orcycloalkyl optionally substituted by 1 or more heteroatoms selected fromthe group consisting of O; N; S; or aryl or heteroaryl optionallysubstituted by 1 or more halogen atoms, C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxy,cyano, amino, alkylamino, dialkylamino, trifluoromethyl, —COOH, or—COOC₁₋₄alkyl.
 11. A method for treating a condition which issusceptible to treatment by modulation of serotonergic systems whereinsaid method comprises administering to an individual in need of suchtreatment, an effective amount of a compound, or an analog or saltthereof, wherein said compound has the following structure:

wherein: R₁ is H, C₁₋₄ alkyl, OH, OC₁₋₄alkyl, —COOH, —COOC₁₋₄alkyl,—O(C═O)OC₁₋₄alkyl, —O(C═O)C₁₋₄alkyl, or —C₁₋₄alkylNR₇R₈ where R₇ and R₈are, independently, H or C₁₋₄ alkyl; R₂ is H, C₁₋₄ alkyl, —OC₁₋₄alkyl,—COOH, or —(C═O)OC₄alkyl; X is O or N; R₃ is H or C₁₋₃ alkyl (if X is anoxygen atom, then R₃ does not exist); R₄, R₅, and R₆ are each,independently, selected from the group consisting of hydrogen, C₁₋₄alkyl, —OC₁₋₄alkyl, halogen atom, hydroxy, cyano, nitro, amino, mono-and di(lower alkyl)amino, aminocarbonyl, arylcarbonylamino,alkylcarbonylamino, lower-alkyl carbonyl, lower-alkyl carbonyloxy,aminosulfonyl, lower-alkylsulfinyl, lower-alkylsulfonyl, lower-alkylthioand mercapto; and wherein L has the formula—C_(n)H_(2n)—X—C_(m)H_(2m)—(CR₉R₁₀)_(p)—(C═O)O—Y, wherein n is aninteger from 1 to 4 inclusive; X is —CH(OH)—, —NH—, —S—, —O—, or adirect bond; m is an integer from 0 to 4 inclusive; p is 0 or 1; R₉ andR₁₀ are, independently, H, C₁₋₄ alkyl, or R₉R₁₀ are linked and togetherform a 5- or a 6-membered cycloalkyl ring; and Y is H, C₁₋₄ alkyl orcycloalkyl optionally substituted by 1 or more heteroatoms selected fromthe group consisting of O; N; S; or aryl or heteroaryl optionallysubstituted by 1 or more halogen atoms, C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxy,cyano, amino, alkylamino, dialkylamino, trifluoromethyl, —COOH, or—COOC₁₋₄alkyl.
 12. The method, according to claim 11, wherein saidcondition is selected from the group consisting of 1) cognitivedisorders, 2) behavioral disorders, 3) mood disorders, and 4) disordersof control of autonomic function.
 13. The method, according to claim 12,wherein said cognitive disorder is Alzheimer's disease.
 14. The method,according to claim 12, wherein said behavioral disorder is selected fromthe group consisting of schizophrenia, mania, obsessive-compulsivedisorder, and psychoactive substance use disorders.
 15. The method,according to claim 12, wherein said mood disorder is selected from thegroup consisting of depression and anxiety.
 16. The method, according toclaim 12, wherein said disorder of control of autonomic function isselected from the group consisting of essential hypertension and sleepdisorders.
 17. The method, according to claim 11, wherein saidindividual is a human.
 18. The method, according to claim 11, whereinR₄, R₅, and R₆ are, independently, selected from the group consisting ofhalo, amino, mono- and dialkylamino, and lower alkyloxy.
 19. The method,according to claim 11, wherein R₄ is methoxy, R₅ is amino ormethylamino, and R₆ is chloro, in the 2-, 4-, and 5-position of thephenyl ring, respectively.
 20. The method, according to claim 11,wherein said compound is selected from the group consisting of:

where IIIa and IIIb are mirror images of each other (enantiomers), andwhere L is defined as shown in Formula (II):

where n=1 to 4, X is a direct bond and Y is hydrogen, lower alkyl, orsubstituted aryl.
 21. The method, according to claim 11, whereinR₁═OCH₃; R₂═H; X═O or N (if X═N, then R₃═H); R₄, R₅, and R₆ are methoxy,amino, and chlorine at the 2, 4, and 5-position of the phenyl ring,respectively.
 22. The method, according to claim 11, wherein bothasymmetric centers are in the cis-configuration.